Design, Synthesis and Biological Activity of Novel Sulfonylurea Derivatives Containing Phenyl-substituted Pyrimidine Moiety†

doi:10.7503/cjcu20140955

Abstract

Abstract:

Acetolactate synthase(ALS) has been regarded as an attractive target for fungicide and herbicide discovery. Furthermore, sulfonylurea(SU) as one of the most active ALS inhibitors were used as herbicides in crops protect. In order to discuss the multi-biological activity of SU, two series of novel SU derivatives containing phenyl-substituted pyrimidine moiety were designed, synthesized and their antifungal activity and herbicidal activity were evaluated. The bioassay results indicated that some title compounds showed excellent antifungal activity against Physalospora piricola and Rhizoctonia cerealis in vitro at the dosage of 50 mg/L. Particularly, compound 9f exhibited more than 65% inhibitory activity against five phytopathogens. On the basis of advanced screening test, the EC₅₀ value of compound 8f against P. piricola was 8.63 mg/L, which was a little higher than Chlorothalonil(EC₅₀=7.33 mg/L), the EC₅₀ value of compounds 8k(5.48 mg/L) and 9k(6.09 mg/L) against R. cerealis were similar to Chlorothalonil(EC₅₀=4.26 mg/L). In addtion, the title compounds showed favorable pre-emergence treatment herbicidal activity against Brassica napus and Amaranthus retroflexus at the dosage of 75 g/ha. For example, compounds 8d and 9d showed 86% and 73% inhibition activity respectively against Brassica napus; compound 9h exhibited 100% herbicidal activity against Amaranthus retroflexus, which was better than that of Chlorsulfuron(96%). The results provided useful information for designing new SU with highly fungicidal activity and herbicidal activity.

Key words: Sulfonylurea, Acetolactate synthase, Phenyl-subsituted pyrimidine, Antifungal activity, Herbicidal activity

CLC Number:

O625.7

TrendMD:

CHEN Wei, WEI Wei, ZHOU Sha, LI Yonghong, ZHANG Xiao, TONG Jun, LI Yuxin, LI Zhengming. Design, Synthesis and Biological Activity of Novel Sulfonylurea Derivatives Containing Phenyl-substituted Pyrimidine Moiety^†[J]. Chem. J. Chinese Universities, 2015, 36(4): 672.

Figures/Tables 10

References 34

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Compd.	m.p.(ref.)/℃	Compd.	m.p.(ref.)/℃	Compd.	m.p.(ref.)/℃
7a	103—104(108—110^[26])	7e	73—74(70—72.5^[29])	7j	140—141(140—141^[27])
7b	123—125(121—123^[26])	7f	146—147(151—153^[26])	7k	103—104(102—104^[31])
7c	99—100(97—98^[27])	7h	162—163(160—164^[30])	7l	137—139(143—144^[27])
7d	151—152(153—155^[28])	7i	124—125(122—125^[30])

Compd.	m.p.(ref.)/℃	Compd.	m.p.(ref.)/℃	Compd.	m.p.(ref.)/℃
7a	103—104(108—110^[26])	7e	73—74(70—72.5^[29])	7j	140—141(140—141^[27])
7b	123—125(121—123^[26])	7f	146—147(151—153^[26])	7k	103—104(102—104^[31])
7c	99—100(97—98^[27])	7h	162—163(160—164^[30])	7l	137—139(143—144^[27])
7d	151—152(153—155^[28])	7i	124—125(122—125^[30])

Compd.	Appearance	Yield (%)	m.p./℃	HRMS(calcd.) m/z, [M+H]⁺	Compd.	Appearance	Yield (%)	m.p./℃	HRMS(calcd.) m/z, [M+H]⁺
8a	White solid	80.3	208—209	368.0946(368.0943)	9a	White solid	81.2	210—211	368.0942(368.0943)
8b	White solid	81.4	214—216	382.1093(382.1100)	9b	White solid	80.7	200—201	382.1099(382.1100)
8c	White solid	76.1	173—174	442.1310(442.1311)	9c	White solid	73.2	188—190	442.1311(442.1311)
8d	White solid	75.2	206—207	414.0872(414.0874)	9d	White solid	73.7	203—205	414.0871(414.0874)
8e	White solid	63.1	204—206	427.1076(427.1076)	9e	White solid	72.1	185—187	427.1077(427.1076)
8f	White solid	74.7	207—209	403.0632(403.0633)	9f	White solid	71.4	189—190	403.0632(403.0633)
8g	White solid	67.9	233—235	448.0482(448.0482)	9g	White solid	70.1	203—205	448.0484(448.0482)
8h	White solid	54.2	187—189	441.1346(441.1345)	9h	White solid	68.7	202—203	441.1346(441.1345)
8i	White solid	74.3	157—158	462.0903(462.0906)	9i	White solid	74.7	160—161	462.0903(462.0906)
8j	White solid	75.4	168—169	468.0953(468.0953)	9j	White solid	71.3	168—169	468.0950(468.0953)
8k	White solid	80.3	191—193	445.1291(445.1294)	9k	White solid	79.7	188—189	445.1290(445.1294)
8l	White solid	78.7	210—211	501.1007(501.1015)	9l	White solid	79.4	183—184	501.1011(501.1015)

Compd.	Appearance	Yield (%)	m.p./℃	HRMS(calcd.) m/z, [M+H]⁺	Compd.	Appearance	Yield (%)	m.p./℃	HRMS(calcd.) m/z, [M+H]⁺
8a	White solid	80.3	208—209	368.0946(368.0943)	9a	White solid	81.2	210—211	368.0942(368.0943)
8b	White solid	81.4	214—216	382.1093(382.1100)	9b	White solid	80.7	200—201	382.1099(382.1100)
8c	White solid	76.1	173—174	442.1310(442.1311)	9c	White solid	73.2	188—190	442.1311(442.1311)
8d	White solid	75.2	206—207	414.0872(414.0874)	9d	White solid	73.7	203—205	414.0871(414.0874)
8e	White solid	63.1	204—206	427.1076(427.1076)	9e	White solid	72.1	185—187	427.1077(427.1076)
8f	White solid	74.7	207—209	403.0632(403.0633)	9f	White solid	71.4	189—190	403.0632(403.0633)
8g	White solid	67.9	233—235	448.0482(448.0482)	9g	White solid	70.1	203—205	448.0484(448.0482)
8h	White solid	54.2	187—189	441.1346(441.1345)	9h	White solid	68.7	202—203	441.1346(441.1345)
8i	White solid	74.3	157—158	462.0903(462.0906)	9i	White solid	74.7	160—161	462.0903(462.0906)
8j	White solid	75.4	168—169	468.0953(468.0953)	9j	White solid	71.3	168—169	468.0950(468.0953)
8k	White solid	80.3	191—193	445.1291(445.1294)	9k	White solid	79.7	188—189	445.1290(445.1294)
8l	White solid	78.7	210—211	501.1007(501.1015)	9l	White solid	79.4	183—184	501.1011(501.1015)

Compd.	¹H NMR(400 MHz), δ	¹³C NMR(101 MHz), δ
8a^a	12.79(s, 1H, SO₂NH), 9.72(br, 1H, CONH-Pyrim), 8.61(s, 1H, Pyrim-H), 8.12(d, J=7.4 Hz, 2H, Ph-H), 7.67—7.63(m, 2H, Ph-H), 7.60(d, J=7.4 Hz, 1H, Ph-H), 7.57—7.51(m, 5H, Ph-H), 2.39(s, 3H, Pyrim-CH₃)	165.10, 160.65, 155.11, 149.64, 139.37, 136.41, 133.59, 130.55, 128.89, 128.84, 128.72, 128.27, 122.61, 16.64
8b^a	12.90(s, 1H, SO₂NH), 10.52(br, 1H, CONH-Pyrim), 8.66(s, 1H, Pyrim-H), 8.23(d, J=7.9 Hz, 1H, Ph-H), 7.66(d, J=5.1 Hz, 2H, Ph-H), 7.57—7.54(m, 3H, Ph-H), 7.48(t, J=7.4 Hz, 1H, Ph-H), 7.37(t, J=7.6 Hz, 1H, Ph-H), 7.25(d, J=7.0 Hz, 1H, Ph-H), 2.55(s, 3H, Ph—CH₃), 2.38(s, 3H, Pyrim-CH₃)	165.14, 160.66, 155.16, 149.37, 137.33, 137.30, 136.37, 133.62, 132.35, 130.93, 130.49, 128.81, 128.72, 126.31, 122.63, 20.01, 16.54
8c^a	12.78(s, 1H, SO₂NH), 10.14(br, 1H, CONH-Pyrim), 8.66(s, 1H, Pyrim-H), 8.14(d, J=7.5 Hz, 1H, Ph-H), 7.75(d, J=6.1 Hz, 2H, Ph-H), 7.62—7.49(m, 4H, Ph-H), 7.10(t, J=7.5 Hz, 1H, Ph-H), 6.98(d, J=8.1 Hz, 1H, Ph-H), 4.01(t, J=4.7 Hz, 2H, OCH₂), 3.25(t, J=4.7 Hz, 2H, OCH₂), 3.01(s, 3H, OCH₃), 2.40(s, 3H, Pyrim-CH₃)	164.85, 160.82, 156.21, 155.30, 149.60, 136.53, 135.43, 131.78, 130.53, 129.01, 128.89, 127.20, 122.35, 120.84, 113.81, 70.04, 68.52, 58.87, 16.68
8d^b	13.39(br, 1H, SO₂NH), 10.93(s, 1H, CONH-Pyrim), 8.69(s, 1H, Pyrim-H), 8.28(d, J=2.6 Hz, 1H, Ph-H), 8.05—7.96(m, 3H, Ph-H), 7.73—7.55(m, 5H, Ph-H), 2.32(s, 3H, Pyrim-CH3)	160.05, 155.52, 148.08, 136.96, 135.95, 133.94, 133.05, 132.93, 130.54, 129.28, 128.95, 128.51, 125.32, 124.73, 123.12, 16.46
8e^b	12.84(br, 1H, SO₂NH), 10.78(s, 1H, CONH-Pyrim), 8.68(s, 1H, Pyrim-H), 8.19(d, J=6.8 Hz, 1H, Ph-H), 7.85—7.68(m, 5H, Ph-H), 7.73—7.55(m, 3H, Ph-H), 3.63(s, 3H, COOCH₃), 2.32(s, 3H, Pyrim-CH₃)
8f^b	13.22(br, 1H, SO₂NH), 10.76(s, 1H, CONH-Pyrim), 8.66(s, 1H, Pyrim-H), 7.71—7.46(m, 9H, Ph-H), 2.31(s, 3H, Pyrim-CH₃)	166.52, 157.82, 155.85, 152.00, 139.75, 133.30, 133.02, 131.54, 129.26, 128.75, 127.50, 127.12, 125.32, 124.73, 123.12, 18.76
Compd.	¹H NMR(400 MHz), δ	¹³C NMR(101 MHz), δ
8g^b	10.89(s, 1H, CONH-Pyrim), 8.78(s, 1H, Pyrim-H), 8.64—8.50(m, 3H, Ph-H, SO₂NH), 8.03—7.98(m, 1H, Ph-H), 7.70—7.57(m, 5H, Ph-H), 2.31(s, 3H, Pyrim-CH₃)	166.52, 155.26, 146.37, 139.75, 137.73, 134.07, 130.59, 129.26, 128.99, 128.75, 127.50, 127.12, 125.32, 124.73, 123.12, 16.43
8h^b	13.00(br, 1H, SO₂NH), 10.78(s, 1H, CONH-Pyrim), 8.72(s, 1H, Pyrim-H), 7.75—7.53(m, 8H, Ph-H, Py-H), 2.94[s, 3H, 1/2 N(CH₃)₂], 2.82[s, 3H, 1/2 N(CH₃)₂], 2.31(s, 3H, Pyrim-CH₃)	167.12, 166.12, 160.83, 160.21, 155.73, 155.06, 150.20, 149.90, 149.70, 137.27, 129.29, 129.02, 128.51, 127.19, 123.09, 38.71, 34.76, 16.49
8i^a	9.29(s, 1H, CONH-Pyrim), 8.67(d, J=2.8 Hz, 1H, Py-H), 8.55(s, 1H, Pyrim-H), 8.19(d, J=7.3 Hz, 1H, Py-H), 7.68(d, J=5.4 Hz, 2H, Ph-H), 7.49—7.32(m, 4H, Ph-H, Py-H, SO₂NH), 7.16—7.08(m, 1H, Ph-H), 3.26(q, J=7.2 Hz, 2H, CH₂), 2.37(s, 3H, Pyrim-CH₃), 1.31(t, J=7.2 Hz, 3H, CH₃)	166.27, 159.94, 156.84, 154.03, 151.34, 142.08, 139.99, 137.72, 129.55, 129.01, 128.38, 122.23, 119.78, 117.27, 49.14, 16.61, 7.15
8j^b	13.03(s, 1H, SO₂NH), 10.80(s, 1H, CONH-Pyrim), 8.60(s, 1H, Pyrim-H), 8.41(d, J=4.4 Hz, 1H, Py-H), 7.66(d, J=6.0 Hz, 2H, Ph-H), 7.56—7.50(m, 4H, Ph-H, Py-H), 7.46(d, J=8.3 Hz, 1H, Ph-H), 4.42(q, J_HF=7.9 Hz, 2H, OCH₂CF₃), 2.39(s, 3H, Pyrim-CH₃)
8k^a	13.12(s, 1H, SO₂NH), 10.58(s, 1H, CONH-Pyrim), 8.63(s, 1H, Pyrim-H), 7.86(s, 1H, Pyrazole-H), 7.80(d, J=5.4 Hz, 2H, Ph-H), 7.54—7.50(m, 3H, Ph-H), 4.33(s, 3H, NCH₃), 4.08(d, J=6.8 Hz, 2H, OCH₂), 2.39(s, 3H, Pyrim-CH₃), 1.15(t, J=6.7 Hz, 3H, CH₃)	165.60, 160.66, 160.30, 154.88, 150.29, 140.28, 138.56, 136.45, 130.41, 129.10, 128.70, 122.84, 116.16, 60.86, 41.54, 16.69, 14.10
8l^b	13.43(br, 1H, SO₂NH), 10.88(s, 1H, CONH-Pyrim), 9.19(d, J=7.0 Hz, 1H, Py-H), 8.65(s, 1H, Pyrim-H), 8.11—7.92(m, 2H, Py-H), 7.84—7.71(m, 3H, Ph-H, Py-H), 7.58—7.40(m, 3H, Ph-H), 3.63(q, J=7.1 Hz, 2H, SO₂CH₂), 2.44(s, 3H, Pyrim-CH₃), 1.20(t, J=7.2 Hz, 3H, CH₃)	165.11, 160.14, 155.34, 144.66, 143.74, 137.00, 130.50, 129.93, 129.42, 129.00, 128.92, 128.54, 127.77, 122.97, 118.90, 116.86, 49.15, 16.46, 7.12
9a^a	13.12(s, 1H, SO₂NH), 8.16(d, J=7.5 Hz, 2H, Ph-H), 8.02(dd, J=6.5, 3.1 Hz, 2H, Ph-H), 7.67—7.50(m, 7H, CONH-Pyrim, Ph-H), 7.30(s, 1H, Pyrim-H), 2.57(s, 3H, Pyrim-CH₃)	169.70, 164.93, 156.64, 149.27, 139.21, 135.16, 133.65, 131.86, 129.30, 128.86, 128.41, 127.22, 111.35, 24.26
9b^a	13.24(s, 1H, SO₂NH), 8.24(d, J=7.9 Hz, 1H, Ph-H), 8.19—7.95(m, 3H, CONH-Pyrim, Ph-H), 7.60—7.44(m, 4H, Ph-H), 7.36(t, J=7.6 Hz, 1H, Ph-H), 7.31(s, 1H, Pyrim-H), 7.27(d, J=7.6 Hz, 1H, Ph-H), 2.66(s, 3H, Ph—CH₃), 2.57(s, 3H, Pyrim-CH₃)	169.41, 165.25, 156.73, 149.12, 137.34, 137.13, 135.08, 133.72, 132.38, 131.90, 131.20, 129.29, 127.22, 126.32, 111.35, 24.25, 20.17
9c^a	13.08(s, 1H, SO₂NH), 8.16(dd, J=7.9, 1.4 Hz, 1H, Ph-H), 8.08(dd, J=6.5, 2.9 Hz, 2H, Ph-H), 7.59—7.52(m, 5H, CONH-Pyrim, Ph-H), 7.33(s, 1H, Pyrim-H), 7.12(t, J=7.7 Hz, 1H, Ph-H), 7.00(d, J=8.3 Hz, 1H, Ph-H), 4.12(t, J=4.7 Hz, 2H, OCH₂), 3.40(s, 2H, OCH₂), 2.97(s, 3H, OCH₃), 2.59(s, 3H, Pyrim-CH₃)	169.96, 164.28, 156.84, 156.19, 149.12, 135.50, 135.16, 132.11, 131.86, 129.35, 127.29, 126.95, 120.81, 113.59, 111.10, 70.18, 68.41, 58.72, 24.31
9d^c	13.81(br, 1H, SO₂NH), 9.64(s, 1H, CONH-Pyrim), 8.43(d, J=7.3 Hz, 1H, Ph-H), 8.22(d, J=7.0 Hz, 2H, Ph-H), 8.05—7.96(m, 3H, Ph-H), 7.73(s, 1H, Pyrim-H), 7.64—7.54(m, 3H, Ph-H), 2.63(s, 3H, Pyrim-CH₃)	164.44, 158.07, 149.80, 149.29, 136.47, 136.20, 134.16, 133.20, 132.53, 132.39, 129.93, 128.27, 127.06, 125.69, 112.07, 24.02
9e^b	13.37(br, 1H, SO₂NH), 10.81(s, 1H, CONH-Pyrim), 8.19—8.03(m, 3H, Ph-H), 7.69—7.55(m, 6H, Ph-H), 7.44(s, 1H, Pyrim-H), 3.69(s, 3H, COOCH₃), 2.30(s, 3H, Pyrim-CH₃)	168.18, 163.65, 157.37, 149.43, 137.52, 134.51, 131.88, 131.41, 130.89, 129.72, 129.53, 129.11, 127.74, 127.22, 111.79, 105.73, 53.30, 23.92
Compd.	¹H NMR(400 MHz), δ	¹³C NMR(101 MHz), δ
9f^a	13.46(br, 1H, SO₂NH), 8.26(d, J=7.5 Hz, 1H, Ph-H), 7.96(d, J=6.8 Hz, 2H, Ph-H), 7.67(br, 1H, CONH-Pyrim), 7.46—7.44(m, 3H, Ph-H), 7.40—7.37(m, 3H, Ph-H), 7.24(s, 1H, Pyrim-H), 2.50(s, 3H, Pyrim-CH₃)	168.18, 163.65, 157.37, 156.57, 149.02, 136.38, 134.67, 132.89, 131.92, 131.65, 129.29, 127.27, 127.20, 111.45, 105.73, 24.24
9g^b	14.18(br, 1H, SO₂NH), 10.98(s, 1H, CONH-Pyrim), 8.80(d, J=2.6 Hz, 1H, Ph-H), 8.52(dd, J=8.7, 2.5 Hz, 1H, Ph-H), 8.16(d, J=6.8 Hz, 2H, Ph-H), 8.02(d, J=8.7 Hz, 1H, Ph-H), 7.62—7.56(m, 3H, Ph-H), 7.47(s, 1H, Pyrim-H), 2.52(s, 3H, Pyrim-CH₃)	157.67, 156.42, 146.46, 137.62, 135.26, 134.14, 133.95, 133.35, 132.45, 129.64, 129.12, 127.70, 127.23, 111.77, 105.72, 23.89
9h^b	13.49(br, 1H, SO₂NH), 10.84(s, 1H, CONH-Pyrim), 8.76(d, J=7.3 Hz, 1H, Py-H), 8.15—8.04(m, 2H, Py-H), 7.77—7.59(m, 5H, Ph-H), 7.37(s, 1H, Pyrim-H), 2.96[s, 3H, 1/2 N(CH₃)₂], 2.85[s, 3H, 1/2 N(CH₃)₂], 2.44(s, 3H, Pyrim-CH₃)
9i^a	9.31(s, 1H, CONH-Pyrim), 8.66(dd, J=4.7, 1.8 Hz, 1H, Py-H), 8.19(dd, J=7.8, 1.8 Hz, 1H, Py-H), 8.10(br, 2H, SO₂NH, Py-H), 7.53(d, J=6.4 Hz, 2H, Ph-H), 7.43(dd, J=7.8, 6.4 Hz, 2H, Ph-H), 7.27(s, 1H, Pyrim-H), 7.12(d, J=7.8 Hz, 1H, Ph-H), 3.26(q, J=7.4 Hz, 2H, SO₂CH₂), 2.57(s, 3H, Pyrim-CH₃), 1.31(t, J=7.4 Hz, 3H, CH₃)	166.27, 159.94, 156.84, 154.03, 151.34, 142.08, 139.99, 137.72, 129.55, 129.01, 128.38, 122.23, 119.78, 117.27, 49.14, 16.61, 7.15
9j^c	13.37(s, 1H, SO₂NH), 9.47(s, 1H, CONH-Pyrim), 8.31(d, J=7.1 Hz, 1H, Py-H), 8.20(d, J=6.5 Hz, 2H, Py-H), 7.74—7.69(m, 2H, Ph-H), 7.58—7.55(m, 4H, Ph-H, Pyrim-H), 4.92(q, J_HF=8.0 Hz, 2H, OCH₂CF₃), 2.58(s, 3H, Pyrim-CH₃)	169.72, 164.34, 157.45, 151.65, 149.47, 145.10, 141.97, 135.60, 131.57, 129.11, 129.05, 127.25, 124.84, 123.88, 110.90, 66.24, 23.24
9k^a	13.58(s, 1H, SO₂NH), 8.09(br, 3H, CONH-Pyrim, Ph-H), 7.88(s, 1H, Pyrazole-H), 7.55—7.54(m, 3H, Ph-H), 7.32(s, 1H, Pyrim-H), 4.36(s, 3H, NCH₃), 4.17(q, J=7.0 Hz, 2H, OCH₂), 2.64(s, 3H, Pyrim-CH₃), 1.22(t, J=7.0 Hz, 3H, CH₃)	169.49, 165.24, 160.62, 156.42, 150.24, 140.25, 138.66, 135.36, 131.69, 129.15, 127.51, 116.21, 111.71, 60.83, 41.53, 24.05, 14.11
9l^b	13.95(s, 1H, SO₂NH), 10.91(s, 1H, CONH-Pyrim), 9.22(d, J=7.0 Hz, 1H, Py-H), 8.21—7.99(m, 3H, Py-H), 7.78(d, J=7.2 Hz, 2H, Ph-H), 7.61—7.56(m, 3H, Ph-H), 7.48(s, 1H, Pyrim-H), 3.64(q, J=7.1 Hz, 2H, OCH₂), 2.53(s, 3H, Pyrim-CH₃), 1.18(t, J=7.2 Hz, 3H, CH₃)	169.68, 163.96, 156.93, 151.81, 145.71, 144.69, 135.47, 132.20, 130.83, 129.51, 128.84, 127.84, 118.91, 118.35, 117.10, 111.73, 49.13, 23.91, 7.11